E-cadherin inhibits nuclear accumulation of Nrf2: implications for chemoresistance of cancer cells

Kim, Won Dong; Kim, Young Woo; Cho, Il Je; Lee, Chang Ho; Kim, Sang Geon

doi:10.1242/jcs.095422

Cited by 67 publications

(55 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with this concept is also the recent finding that oxidative stress is causing disruption of adherens junctions as a consequence of loss of proteinprotein interactions between b-catenin and E-cadherin [52,68]. In addition, Nrf2, a regulator of anti-oxidant gene expression, might be recruited to E-cadherin thereby inactivating Nrf2 and favoring oxidative stress and carcinogenesis [69]. Nrf2 has been linked to the expression of heme oxygenase-1, the key control enzyme of heme degradation generating end products that act as anti-oxidants [70].…”

Section: Discussionmentioning

confidence: 74%

Pathological implications of cadherin zonation in mouse liver

Hempel

Schmitz

Winkler

et al. 2015

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Both acute and chronic liver diseases are associated with ample re-modeling of the liver parenchyma leading to functional impairment, which is thus obviously the cause or the consequence of the disruption of the epithelial integrity. It was, therefore, the aim of this study to investigate the distribution of the adherens junction components E- and N-cadherin, which are important determinants of tissue cohesion. E-cadherin was expressed in periportal but not in perivenous hepatocytes. In contrast, N-cadherin was more enriched towards the perivenous hepatocytes. In agreement, β-catenin, which links both cadherins via α-catenin to the actin cytoskeleton, was expressed ubiquitously. This zonal expression of cadherins was preserved in acute liver injury after treatment with acetaminophen or partial hepatectomy, but disrupted in chronic liver damage like in non-alcoholic steatohepatitis (NASH) or α1-antitrypsin deficiency. Hepatocyte proliferation during acetaminophen-induced liver damage was predominant at the boundary between the damaged perivenous and the intact periportal parenchyma indicating a minor contribution of periportal hepatocytes to liver regeneration. In NASH livers, an oval cell reaction was observed pointing to massive tissue damage coinciding with the gross impairment of hepatocyte proliferation. In the liver parenchyma, metabolic functions are distributed heterogeneously. For example, the expression of phosphoenolpyruvate carboxykinase and E-cadherin overlapped in periportal hepatocytes. Thus, during liver regeneration after acute damage, the intact periportal parenchyma might sustain essential metabolic support like glucose supply or ammonia detoxification. However, disruption of epithelial integrity during chronic challenges may increase susceptibility to metabolic liver diseases such as NASH or vice versa. This might suggest the regulatory integration of tissue cohesion and metabolic functions in the liver.

show abstract

Section: Discussionmentioning

confidence: 74%

Pathological implications of cadherin zonation in mouse liver

Hempel

Schmitz

Winkler

et al. 2015

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…5b and Additional file 1: Figure S4B). It has been reported that Nrf2 activation could promote cancer metastasis by modulating epithelial-mesenchymal transition (EMT) [24]. Nrf2 knocked-down in cancer cells before TEM CM stimulation was performed to illustrate the relationship between TEM-induced cancer cell Nrf2 activation and EMT (Fig.…”

Section: Resultsmentioning

confidence: 99%

Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction

et al. 2018

View full text Add to dashboard Cite

BackgroundThe M2 phenotype of tumor-associated macrophages (TAM) inhibits the anti-tumor inflammation, increases angiogenesis and promotes tumor progression. The transcription factor Nuclear Factor (erythroid-derived 2)-Like 2 (Nrf2) not only modulates the angiogenesis but also plays the anti-inflammatory role through inhibiting pro-inflammatory cytokines expression; however, the role of Nrf2 in the cancer cell and macrophages interaction is not clear.MethodsHepatocellular carcinoma cells (Hep G2 and Huh 7) and pancreatic cancer cells (SUIT2 and Panc-1) were co-cultured with monocytes cells (THP-1) or peripheral blood monocytes derived macrophages, then the phenotype changes of macrophages and epithelial-mesenchymal transition of cancer cells were detected. Also, the role of Nrf2 in cancer cells and macrophages interaction were investigated.ResultsIn this study, we found that cancer cells could induce an M2-like macrophage characterized by up-regulation of CD163 and Arg1, and down-regulation of IL-1b and IL-6 through Nrf2 activation. Also, Nrf2 activation of macrophages promoted VEGF expression. The Nrf2 activation of macrophages correlated with the reactive oxygen species induced by cancer cells derived lactate. Cancer cells educated macrophages could activate Nrf2 of the cancer cells, in turn, to increase cancer cells epithelial-mesenchymal transition (EMT) through paracrine VEGF. These findings suggested that Nrf2 played the important role in the cancer cells and macrophages interaction.ConclusionsMacrophage Nrf2 activation by cancer cell-derived lactate skews macrophages polarization towards an M2-like phenotype and educated macrophages activate Nrf2 of the cancer cells to promote EMT of cancer cells. This study provides a new understanding of the role of Nrf2 in the cancer cell and TAM interaction and suggests a potential therapeutic target.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0262-x) contains supplementary material, which is available to authorized users.

show abstract

“…Overexpression of E-cadherin results in inhibition of Nrf2 nuclear translocation (39). We therefore evaluated E-cadherin levels in an attempt to explain the inability of CysLTr1 2/2 mice to translocate Nrf2.…”

Section: Cyslts Induce Nrf2 Nuclear Translocation Through Indirect Mementioning

confidence: 99%

CysLT1 Receptor Is Protective against Oxidative Stress in a Model of Irritant-Induced Asthma

McGovern

Goldberger

Chen

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

The bronchoconstrictive and proinflammatory properties of cysteinyl leukotrienes (cysLTs) in allergic asthma mediate their effects predominantly through the cysLT1 receptor (cysLT1R). However, the role of cysLTs and cysLT1R in innate immune-triggered asthma is largely unexplored. We explored the synthesis of cysLTs and cysLT1R as determinants of airway responses in an oxidative stress–induced model of irritant asthma. Wild-type (WT) mice exposed to 100 ppm Cl2 for 5 min had airway neutrophilia, increased cysLT production, and pulmonary expression of cysLT-related biosynthetic genes. CysLT1R-deficient (CysLTr1−/−) mice that were exposed to Cl2 demonstrated airway hyperresponsiveness to inhaled methacholine significantly greater than in WT BALB/c mice. Compared to WT mice, airway neutrophilia and keratinocyte chemoattractant production levels were higher in CysLTr1−/− mice and airway hyperresponsiveness was ameliorated using a granulocyte depletion Ab. CysLTr1−/− mice also demonstrated prolonged bronchial epithelial cell apoptosis following Cl2. WT mice showed increased antioxidant and NF erythroid 2–related factor 2 (Nrf2) gene expression, Nrf2 nuclear translocation in bronchial epithelial cells, and increased reduced glutathione/oxidized glutathione following Cl2 exposure whereas CysLTr1−/− mice did not. Furthermore, CysLTr1−/− mice demonstrated increased pulmonary E-cadherin expression and soluble E-cadherin shedding compared with WT mice. Loss of a functional cysLT1R results in aberrant antioxidant response and increased susceptibility to oxidative injury, apparently via a cysLT1R-dependent impairment of Nrf2 function.

show abstract

E-cadherin inhibits nuclear accumulation of Nrf2: implications for chemoresistance of cancer cells

Cited by 67 publications

References 41 publications

Pathological implications of cadherin zonation in mouse liver

Pathological implications of cadherin zonation in mouse liver

Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction

CysLT1 Receptor Is Protective against Oxidative Stress in a Model of Irritant-Induced Asthma

Contact Info

Product

Resources

About